EP0904298A1 - Substantially uncrosslinked carboxymethyl starch, process for the preparation thereof, use as a retarding agent and a retarding drug - Google Patents
Substantially uncrosslinked carboxymethyl starch, process for the preparation thereof, use as a retarding agent and a retarding drugInfo
- Publication number
- EP0904298A1 EP0904298A1 EP97926983A EP97926983A EP0904298A1 EP 0904298 A1 EP0904298 A1 EP 0904298A1 EP 97926983 A EP97926983 A EP 97926983A EP 97926983 A EP97926983 A EP 97926983A EP 0904298 A1 EP0904298 A1 EP 0904298A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carboxymethyl starch
- uncross
- starch
- retarding
- linked
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B31/00—Preparation of derivatives of starch
- C08B31/08—Ethers
- C08B31/12—Ethers having alkyl or cycloalkyl radicals substituted by heteroatoms, e.g. hydroxyalkyl or carboxyalkyl starch
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Definitions
- the invention relates to an almost uncrosslinked carboxymethyl starch, a process for its preparation, the use of this modified carboxymethyl starch
- Carboxymethyl starches with different degrees of cross-linking and different viscosities have long been used in different areas of the food and pharmaceutical industry as well as the cosmetics industry, cigarette industry and for special technical applications.
- Carboxymethyl starches are manufactured, among others. by reacting native starch with sodium hydroxide solution and monochloroacetic acid in the presence of alcoholic swelling inhibitors. With the addition of z. For example, epichlorohydrin or dichloroacetic acid then crosslinks the carboxymethyl starch. The crosslinking serves to improve and stabilize the viscosity and swelling properties of the carboxymethyl starch. White, flowable, very hygroscopic powders that swell in water are achieved. Either milky, cloudy suspensions or gels are formed. Because of the swelling properties of cross-linked carboxymethyl starches, these starches are used in pharmaceuticals, among other things, as tablet disintegrants or disintegrants.
- the object of the invention is therefore to produce a new carboxymethyl starch.
- the object is achieved by an almost uncross-linked carboxymethyl starch which is distinguished by a low viscosity, the gel-like, not milky cloudy, but clear solution of which does not sediment.
- Almost uncross-linked carboxymethyl starch is understood according to the invention to mean carboxymethyl starch which is obtained by etherification of native starch in the presence of alcoholic swelling inhibitors with the exclusion of crosslinking agents and is not subjected to any additional crosslinking.
- This almost uncross-linked carboxymethyl starch forms clear gels in aqueous solutions that do not sediment, have low viscosity and are low sensitivity to shear stress. Furthermore, the viscosity of aqueous solutions of the carboxymethyl starch according to the invention can be freely adjusted.
- the almost uncrosslinked carboxymethyl starch according to the invention is prepared in such a way that native, uncrosslinked starch is suspended in almost anhydrous alcoholic solvent and alkalized with NaOH and then etherified using monochloroacetic acid at a temperature of 30 to 40 ° C.
- the crude product thus obtained is neutralized with an acid, preferably acetic acid or hydrochloric acid, desalted by washing with an aqueous alcoholic solvent, then washed several times with an almost anhydrous alcoholic solvent and at temperatures below 80 ° C, preferably at 60-80 ° C, about 2 to Gently dried under vacuum for 3 hours.
- the reaction is carried out with the exclusion of chemical crosslinking agents at temperatures below 80 ° C in all process stages so that physical crosslinking of the starch used and the etherified starch derivative is almost impossible.
- the neutralization following the etherification causes the carboxymethyl substituents to be converted from the Na form to the H form.
- Intermolecular crosslinking is possible via the H form, only very slight crosslinking taking place using the process according to the invention.
- Figure 1 shows such an intermolecular crosslinking.
- the carboxymethyl starch according to the invention can be used in many ways due to its new properties. It is surprising that the invention, almost uncrosslinked
- Carboxymethyl starch is suitable as an auxiliary agent for retardation in medicinal products.
- Modified carboxymethyl starches have hitherto been used as tablet disintegrants because of their swellability.
- a pharmaceutical preparation can be delayed
- Formulate drug release so that it contains, in addition to the pharmacological active ingredient and conventional auxiliaries, such as filler, flow agent, lubricant, etc., 5 to 25% by weight of virtually uncrosslinked carboxymethyl starch.
- auxiliaries such as filler, flow agent, lubricant, etc.
- Fig. 5 Viscosity diagrams of product according to exemplary embodiment 1
- Fig. 6 Viscosity diagrams UAP 5000
- Fig. 7 Diagram of active ingredient release Diclofec-Na
- Fig. 8 diagram of active ingredient release in dry and moist granulation.
- Fig. 9 diagram of active ingredient release Verapamil.
- 10 diagram of active ingredient release theophylline
- Viscosity measured with the cone-plate system (4 cm diameter, 2 ° cone, 54 ⁇ m
- FIG. 2 shows an appearance that matches that of native potato starch.
- the grain shape typical of potato starch has been preserved.
- the FTIR spectrum added as FIG. 3 corresponds to the IR spectra of known carboxymethyl starches. Nevertheless, the carboxymethyl starch according to the invention differs.
- FIGS. 5 and 6 contain viscosity diagrams of UAP 5000 and the product produced according to embodiment 1, here designated UAP 100.
- the viscosity is plotted against time at constant shear rate.
- the viscosity data and the shear rate are shown logarithmically in the diagram at the top right (shear rate curve).
- the diagrams shown in FIGS. 5-6 below show on the one hand the function of the viscosity at constant shear rate and on the other hand the function at variable shear rate.
- a Carri Med CSL 100 measuring instrument from TA-Instruments was used as the measuring instrument.
- the viscosity of the gel as a function of the speed can be recognized very well from the shear rate curve. This is also a common method to identify sensitivity to shear stress.
- K denotes the quasi-viscosity at no shear stress
- a represents the sensitivity to shear stress.
- log ⁇ log K - a • log ⁇ ).
- the regression coefficient R is a measure of the accuracy of the regression.
- the products UAP 100 and UAP 5000 differ not only in their respective viscosity behavior as a function of the shear rate, but also in their shear rate profiles. It can clearly be seen that UAP 5000 has a much more viscous behavior, but is more sensitive to shear stress, which can be seen from the steepness in the figure at the top right (Fig. 6). This is also expressed in the corresponding K and a values, which can be seen in the two lower figures. It can be seen that the K value at
- Product UAP 5000 is approx. 10x higher than product UAP 100.
- the viscosity of the product according to the invention can also be freely adjusted in solution.
- carboxymethyl starch produced according to embodiment 1 is mixed with the active pharmaceutical ingredient diclofenac-Na, magnesium stearate as a lubricant, highly disperse SiO 2 (Aerosil) as a flow agent and microcrystalline cellulose (Microcel 101 SP) as a filler in the following composition, the proportions of carboxymethyl starch (CMS ) and microcrystalline cellulose are varied:
- tablets are manufactured in the following way:
- the substances are dispersed through a sieve with a mesh size of 0.5 mm, mixed and compressed on an eccentric tabletting machine (Korsch EK 0) into tablets (biplan with facet edge, 10 mm diameter). With a weight of 300 mg / tablet, the active substance content is 100 mg.
- Each 10 tablets are tested for their compressive strength with a hardness tester (Heberlein) using the force application method (tablet lying on the horizontal between two compressing jaws).
- the mean value is calculated from 10 individual values.
- the active ingredient release of Diclofenac-Na 100 mg tablets is tested according to the USP paddle method in 900 ml phosphate buffer at pH 7.2 and 50 rpm for 8 hours.
- the released diclofenac Na content is measured photometrically.
- the tablets produced according to Example 2 have the following data:
- carboxymethyl starch produced according to embodiment 1, tablets are produced by the wet granulation and dry granulation methods.
- the substances are mixed, sieved and compacted using a 2-roller compactor and crushed (granulated) using a sieving machine (sieve 1.25 mm) with an oscillating star rotor.
- the granules are pressed into tablets (biplan with a 10 mm diameter facet edge) on an eccentric tableting machine (Korsch EK 0). Tablets with a weight of 300 mg, hardness 9.1 kg, abrasion resistance 0.6% are reached (determination based on the methods shown in embodiment 2).
- 8 shows the active ingredient releases of diclofenac-Na according to the USP paddle method (50 rpm, 900 ml phosphate buffer, pH 7.2). It can be seen that the active ingredient diclofenac-Na is released with a delay over a period of 8 hours.
- tablets with the pharmacological active ingredient verapamil are prepared in the following composition:
- Aerosil 200 0.7 Ma%
- the tablets are produced once in the same way as in exemplary embodiments 2 and 3 by direct tabletting and by dry granulation.
- the tablets produced contain 240 mg verapamil per tablet and have the following data according to the determination methods given in embodiment 2:
- the active ingredient releases are shown graphically according to the USP paddle method (100 rpm, 900 ml, pH 1, 2, 0 ... 2 h then pH 6.8).
- the active ingredient Verapamil-HCl is released with a delay of 8 hours.
- Example 2 Using direct tableting as in Example 2, a tablet is prepared using the carboxymethyl starch (CMS) obtained in Example 1 and the active ingredient theophylline, with the following composition: Theophylline 62.5% by mass
- Aerosil 200 1.0 Ma%
- the tablets contain 200 mg of theophylline per tablet and have the following data:
- FIG. 10 shows graphically the release of active substance over time, determined according to the USP paddle method (50 rpm, 900 ml, pH 1.2, 0... 2 h then pH 6.8).
- the active ingredient theophylline is released with a delay of 8 hours.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Materials Engineering (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19622790 | 1996-06-06 | ||
DE19622790A DE19622790A1 (en) | 1996-06-06 | 1996-06-06 | Almost uncrosslinked carboxymethyl starch, process for its preparation, use of this modified starch as a retardant and a retarding pharmaceutical composition |
PCT/DE1997/001138 WO1997046592A1 (en) | 1996-06-06 | 1997-06-06 | Substantially uncrosslinked carboxymethyl starch, process for the preparation thereof, use as a retarding agent and a retarding drug |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0904298A1 true EP0904298A1 (en) | 1999-03-31 |
EP0904298B1 EP0904298B1 (en) | 2002-04-03 |
Family
ID=7796345
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97926983A Revoked EP0904298B1 (en) | 1996-06-06 | 1997-06-06 | Substantially uncrosslinked carboxymethyl starch, process for the preparation thereof, use as a retarding agent and a retarding drug |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0904298B1 (en) |
AT (1) | ATE215566T1 (en) |
DE (2) | DE19622790A1 (en) |
WO (1) | WO1997046592A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005074976A1 (en) * | 2004-02-09 | 2005-08-18 | Transfert Plus Société En Commandite | Composition comprising polymeric material and uses thereof |
JP5547966B2 (en) * | 2006-12-15 | 2014-07-16 | カンピナ ネーデルランド ホールディング ビー.ブイ. | Sustained release excipient and use thereof |
EP1935411A1 (en) * | 2006-12-15 | 2008-06-25 | Campina Nederland Holding B.V. | Slow release excipient and its use |
CN101610757B (en) * | 2006-12-15 | 2013-08-28 | 堪匹那荷兰控股公司 | Extended release excipient and its use |
CN104888263B (en) | 2008-01-14 | 2018-11-30 | 北京环球利康科技有限公司 | Biocompatible hemostatic prevents adhesion, promoting healing, the closed modified starch material of surgery |
US9376648B2 (en) | 2008-04-07 | 2016-06-28 | The Procter & Gamble Company | Foam manipulation compositions containing fine particles |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2599620A (en) * | 1950-08-31 | 1952-06-10 | Du Pont | Carboxymethyl ethers |
JPS6143601A (en) * | 1984-08-07 | 1986-03-03 | Dai Ichi Kogyo Seiyaku Co Ltd | Preparation of carboxymethyl starch having high etherification degree |
CH678697A5 (en) * | 1989-04-03 | 1991-10-31 | Warner Lambert Co |
-
1996
- 1996-06-06 DE DE19622790A patent/DE19622790A1/en not_active Withdrawn
-
1997
- 1997-06-06 WO PCT/DE1997/001138 patent/WO1997046592A1/en not_active Application Discontinuation
- 1997-06-06 AT AT97926983T patent/ATE215566T1/en not_active IP Right Cessation
- 1997-06-06 EP EP97926983A patent/EP0904298B1/en not_active Revoked
- 1997-06-06 DE DE59706873T patent/DE59706873D1/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
See references of WO9746592A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP0904298B1 (en) | 2002-04-03 |
WO1997046592A1 (en) | 1997-12-11 |
DE59706873D1 (en) | 2002-05-08 |
ATE215566T1 (en) | 2002-04-15 |
DE19622790A1 (en) | 1997-12-11 |
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